Acute Respiratory Distress Syndrome

CliniCal FoCus Review Jerrold H. levy, M.D., F.a.H.a., F.C.C.M., editor

Contemporary Management and Novel Approaches during COVID-19
George W. Williams, M.D., Nathaniel K. Berg, B.S., Alexander Reskallah, M.D., Xiaoyi Yuan, Ph.D., Holger K. Eltzschig, M.D., Ph.D.

Acute respiratory distress syndrome (ARDS) is de ned as hypoxemia secondary to a rapid onset of noncardio- genic pulmonary edema.1 Etiologic risk factors for ARDS encompass both direct and indirect lung injuries including but not limited to pneumonia, sepsis, noncardiogenic shock, aspiration, trauma, contusion, transfusion, and inhalation injuries.Although clinical recognition and management of ARDS have improved signi cantly over the past 25 yr, it is still a leading cause of death in critically ill patients, with mortality rates consistently reported around 30 to 40%.2 An important factor in the high mortality rate in ARDS is that treatment is mainly focused on clinical management and no targeted therapies currently exist. Furthermore, ARDS management is often challenging as it commonly occurs in a clinical setting of multiple organ failure and can also lead to the development of nonpulmonary organ injury, such as acute kidney injury.3 Recently, the pandemic caused by coronavirus disease 2019 (COVID-19), which results from infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has led to a dramatic inci- dence in COVID-19–related ARDS. Thirty to forty per- cent of COVID-19 hospitalized patients develop ARDS, and it is associated with 70% of fatal cases.4,5 At the time of this writing (July 31, 2020), there are more than 4.5 million COVID-19 cases and 152,000 related deaths in the United States.6 Here, we describe select management strategies that have become foundations of ARDS clinical management and provide an update of emerging approaches for the treatment of ARDS related to COVID-19.

Clinical Treatment Concepts

Nationally Organized Research Consortia to Study ARDS

To improve outcomes and develop treatment protocols for ARDS, the National Heart, Lung, and Blood Institute of the National Institutes of Health (Bethesda, Maryland) funded a series of multicenter clinical trials, which formed a research collaboration called the ARDS Network (http:// ardsnet.org, accessed July 22, 2020).7 Beginning in 1994, the network studies enrolled more than 5,500 patients, included 10 clinical trials and one observational study, led

G.W.W. and N.K.B. contributed equally to this article.

to the development of new clinical parameters such as

8
ventilator-free days, and resulted in seminal advances that

have helped to shape current ARDS management. National Heart, Lung, and Blood Institute–funded clinical trials con- tinue currently under the Prevention and Early Treatment of Acute Lung Injury (PETAL) Network (http://petalnet. org, accessed July 22, 2020). Figure 1 and table 1 brie y summarize the results and implications of the results for ARDS and PETAL Network trials, along with other important trials performed internationally.

Small Tidal Volumes

Among the best-established guidelines in managing ARDS patients is the use of small tidal volumes during mechanical ventilation ( g. 1). In 2000, investigators from the ARDSNet Lower Tidal Volume (ARMA) trial reported signi cantly decreased rates of mortality (31.0% vs. 39.8%) in ARDS patients ventilated with 6 ml/kg of predicted body weight tidal volumes versus those with 12ml/kg of predicted body weight.9 While small tidal volume ventilation remains a tenet of lung-protective ventilation during ARDS, recent e orts have sought to determine whether small tidal volumes play a lung-pro- tective role more broadly in all critically ill ventilated patients. In 2018, the Protective Ventilation in Patients Without ARDS (PReVENT) trial indicated that venti- lation with low tidal volumes may not be more e ective than intermediate volumes in non-ARDS intensive care unit patients.10

Positive End-expiratory Pressure

In their seminal 1967 report of ARDS cases,Ashbaugh et al. reported that improvement of hypoxemia and atelectasis was achieved by the implementation of positive end-ex- piratory pressure (PEEP).11 Since then, PEEP continues to be employed in ARDS management and remains the focus of many clinical research e orts. Conceptually, PEEP is administered in order to reduce atelectrauma (repetitive opening and closing of alveoli) by recruiting collapsed alveoli.12 Much attention has been directed at

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Submitted for publication June 10, 2020. Accepted for publication August 31, 2020. From the Department of Anesthesiology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas.

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Fig. 1. A summary of 25 yr of acute respiratory distress syndrome (ARDS) intervention trials. Interventions are chronologically displayed with corresponding clinical trials italicized underneath and color-coded to denote clinical ef cacy. Interventions that have clear clinical ef cacy, in blue boxes, include the use of small tidal volumes,9 prone positioning,20 and restrictive uid administration,37 which have demonstrated clear mortality or ventilator-free days bene ts. Interventions in gray boxes include those that have mixed results from different trials, as is the case for conservative oxygen treatment32,33,75 and early neuromuscular blockade.38,39 This category (gray boxes) also includes interventions with indeterminate results, such as the case for positive end-expiratory pressure (PEEP)15—itself is a component of lung-protective ventilation, but the appropriate amount to use is still contended—or those that have value in ARDS patients aside from improving ARDS outcomes, such as early trophic enteral nutrition to prevent gastric intolerance40 and extracorporeal membrane oxygenation as a rescue therapy.35,36 In orange boxes are interventions that failed to demonstrate improvements in ARDS outcomes, such as antifungals, lisofylline, albuterol, simvastatin, vitamin C, and vitamin D.41–47,76,77 Dexamethasone is also listed in this category given that the DEXA-ARDS trial was conducted in an unblinded fashion28 and previous randomized trials showed no clinical ef cacy for steroid administration in ARDS. Methylprednisolone,27 rosuvastatin,49 and omega-3 fatty acids,48 listed in red boxes, have been shown to cause potential harm in randomized controlled trials. Current, ongoing, or planned trials and emerging therapeutic targets are displayed in green.

the levels at which PEEP is applied, with clinical evi- dence yielding mixed results ( g. 1). Several trials that report protective bene ts from higher versus lower targets of PEEP employed higher tidal volumes in their con- trol (lower PEEP) groups, which perhaps introduced bias in their conclusions.13,14 Trials that have controlled for low tidal volumes (6 ml/kg), including the 2004 ARDS Network Higher vs Lower PEEP (ALVEOLI) trial, have failed to establish a survival bene t for higher PEEP.15,16 Subgroup analysis does, however, suggest that higher PEEP is associated with improved survival among the subgroup of patients with ARDS who objectively respond to increased PEEP (patients who show improved oxygen- ation in response to increased PEEP).17 Still, it has yet

to be demonstrated whether survival in selected patients improves with increased PEEP in large randomized trials.

Prone Positioning

Bene cial e ects of prone positioning during mechanical ventilation of ARDS patients are considered in order to establish a more even distribution of gravitational force in pleural pressure, allowing for improved ventilation of the dorsal lung space18 and limiting overdistention of alveoli.19 In 2013, Guérin et al. reported the results of the Proning Severe ARDS Patients (PROSEVA) trial in which severe ARDS patients (Pao2/fractional inspired oxygen tension [Fio2] less than 150 on Fio2 of at least 0.6) were random- ized to prone positioning for a minimum of 16h/day.

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Williams et al.

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Table 1. Summarized Results of Select Large-scale Intervention Trials Aimed at Improving Outcomes in Patients with Acute Respiratory Distress Syndrome

Clinical intervention

Small tidal volumes

PEEP
Prone positioning

Steroids

Conservative oxygenation

Trial name

The 2000 Acute Respiratory Distress Syndrome Network trial (ARMA)9

Higher vs. Lower PEEP (ALVEOLI)15 Proning Severe ARDS Patients

(PROSEVA) trial20

Late Steroid Rescue Study (LaSRS)27

Dexamethasone Treatment for the Acute Respiratory Distress Syndrome

(DEXA-ARDS)28

Normal Oxygenation Versus Hyperoxia in the Intensive Care Unit (ICU) (OXYGEN-ICU) trial32

Intensive Care Unit Randomized Trial Comparing Two Approaches to Oxygen Therapy (ICU-ROX)75

Liberal or Conservative Oxygen Therapy for ARDS (LOCO2)33

Conventional Ventilatory Support vs. ECMO for Severe Adult Respiratory Failure (CESAR)35

Rescue Lung Injury in Severe ARDS (EOLIA)36

Fluids and Catheters Treatment Trial (FACTT)37

ARDS et Curarisation Systematique (ACURASYS)38

Reevaluation of Systemic Early Neuromuscular Blockade (ROSE)39

study Groups

Low tidal volume (6 ml/kg of predicted body weight) or
Traditional tidal volume
(12 ml/kg of predicted body weight)

Low PEEP
or
High PEEP (inspiratory plateau pressure of 28–30)

Supine position or
Prone position
(at least 16 h/day)

In patients 7–28 days after onset of ARDS: Placebo
or
Methylprednisolone

Standard of care or Dexamethasone

Conventional oxygen: Pao2 up to 150 mmHg or SaO2 up to 97 to 100%

or
Conservative oxygen:
Pao2 70 to 100 mmHg or SaO2 of 94 to 98%

Usual oxygen therapy: no upper limit to Fio2 or SaO2 or
Conservative oxygen therapy: SaO2 between 90 and

97%

Liberal oxygenation:
target Pao2 90–105 mmHg; SaO2 > 96% or
Conservative oxygenation:
target Pao2 55-70 mmHg; SaO2 88–92%

Conventional management
or
Extracorporeal membrane oxygenation

Early extracorporeal membrane oxygenation
or
Conventional mechanical ventilation with extracorporeal

membrane oxygenation as a rescue therapy

Liberal uids (CVP 10–14) or
Conservative uids
(CVP < 4)

Patients rst sedated to a Ramsay sedation score of 6, then given:

Placebo
or Cisatracurium

Usual care: lightly sedated
or
Early neuromuscular blockade: deep sedation and cisatracurium

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outcomes

Reduction in 180-day mortality 31.0% vs. 39.8% (P = 0.007)

No change in death before discharge 24.9% vs. 27.5% (P = 0.48)

Reduction in 28-day mortality 16.0% vs. 32.8% (P < 0.001)

No change in 60-day mortality
28.6% vs. 29.2%
and
Increased mortality in patients receiving methylpred-

nisolone at least 14 days after ARDS diagnosis Increase in ventilator-free days

12.3 vs. 7.5 days (P < 0.0001)
and
Reduction in all-cause mortality at day 60 21% vs. 36%

Reduction in ICU mortality 11.6% vs. 20.2% (P = 0.01)

No change in ventilator-free days 21.3 vs. 22.1 days
and
No change in 180-day mortality 35.7% vs. 34.5%

Increased mortality in conservative oxygen group 34.3% vs. 26.5%

Increased survival without severe disability at 6 months

63% vs. 47%
Non–statistically signi cant reduction in mortality

35% vs. 46% (P = 0.09)
No change in all-cause mortality at 60 days

25.5% vs. 28.4% (P = 0.30)
Adjusted hazard ratio for death at 90 days of

0.68 in NM blockade group (P = 0.04)

No change in 90-day mortality 42.5% vs. 42.8%

(Continued )

Extracorporeal membrane

oxygenation

Fluid restriction

Early neuromus- cular blockade

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Table 1. (Continued) Clinical

intervention

Statin treatment

Trial name

Simvastatin in the Acute Respiratory Distress Syndrome (HARP-2)47

Statins for Acutely Injured Lungs from Sepsis (SAILS)49

study Groups

Placebo
or
Simvastatin for maximum 28 days

Placebo
or
Rosuvastatin for maximum 28 days

Trophic enteral feeding:
10–20 kcal/h
or
Full enteral feeding: 25–30 kcal/kg per day of nonpro-

tein calories and 1.2 to 1.6 g/kg per day of protein

Enteral supplementation of omega-3 fatty acids, γ-lino- lenic acid, and antioxidants

or
An isocaloric control

Matched placebo (5% dextrose in water)
or
Vitamin C 50 mg/kg total body weight every 6 h for 96 h

Placebo
or
Vitamin D3

Aerosolized albuterol (5 mg) or

Placebo (aerosolized saline)

Ketoconazole, 400 mg/day or
Placebo

Lisofylline (3 mg/kg with a maximum dose of 300 mg) or
Placebo

outcomes

No signi cant change in ventilator-free days 12.6 vs. 11.5 days
or
28-day mortality

22% vs. 26.8%
No change in 60-day mortality

28.5% vs. 24.9%
and
Fewer days free of renal or hepatic failure

No change in ventilator-free days 14.9 vs. 15 days and
No change in 60-day mortality
23.2% vs. 22.2%

Reduction in ventilator-free days
14.0 vs. 17.2 days
and
Non-statistically signi cant increase in mortality

26.6% vs. 16.3% (P = 0.054)
No change in Sequential Organ Failure Assessment

(SOFA) score 3 vs. 3.5

No difference in 90-day mortality 23.5% vs. 20.6% (P = 0.26)

No difference in ventilator-free days 14.4 vs. 16.6 and
No difference in mortality before hospital discharge 23% vs. 17.7%

No difference in in-hospital mortality 34.1% vs. 35.2%

No difference in mortality 31.9% vs. 24.7% (P = 0.215)

Vitamins, nutrition, Early vs. Delayed Enteral Nutrition

and supplements

β2-Agonist Antifungals

Lisofylline

(EDEN)40

Omega Nutrition Supplement Trial (Omega)48

Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury

(CITRIS-ALI)76
Vitamin D to Improve Outcomes

by Leveraging Early Treatment (VIOLET)77

Albuterol for the Treatment of ALI (ALTA)41

Ketoconazole for ALI/ARDS (KARMA)46

Lisofylline for ALI/ARDS (LARMA)45

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ARDS, acute respiratory distress syndrome; CVP, central venous pressure; Fio2, fractional inspired oxygen tension; ICU, intensive care unit; PEEP, positive end-expiratory pressure; Sao2, arterial oxygen saturation.

Patients randomized to prone positioning had a 50% reduc- tion in mortality (16% vs. 32.8%) at 28 days ( g. 1).20 A recent meta-analysis corroborates these results and sup- ports the survival bene ts of prolonged prone positioning (greater than 12 h) in patients with severe ARDS.21 Despite these encouraging results in reducing mortality with the use of prone positioning, data from a large, multinational pro- spective observational study indicate that the maneuver was employed in only 16.3% of severe ARDS patients.2 Possible reasons for this low implementation could be attributed to the relative complexity and logistic considerations of prone positioning (e.g., multiple persons required for the maneuver, increased workloads, management of secretions, and nutri- tion) or to the inherent risks of the procedure such as endo- tracheal tube and vascular line displacement. Nonetheless,

the use of prone positioning for more than 12 h/day remains a strong recommendation for patients with severe ARDS.22

Although the e cacy of prone positioning is almost exclusively suggested in patients with Pao2/Fio2 ratios of 150 or less, trials that failed to show e cacy in mild and moderate ARDS are largely underpowered and failed to administer prone positioning for recommended lengths of time.23 As such, randomized trials implementing early prone positioning in mild to moderate cases of ARDS are neces- sary to determine any survival bene ts and to make recom- mendations for clinical implementation.

Steroids in Non–COVID-19 ARDS

In the report of ARDS patients by Ashbaugh et al. in 1967, it was suggested that corticosteroids appeared to have

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clinical value in cases associated with fat emboli and viral pneumonia.11 Randomized control trials conducted in the 1980s have since demonstrated that early administration of methylprednisolone did not result in improved ARDS sur- vival.24,25 However, in 1998 a prospective trial by Meduri et al. showed an improved outcome in ARDS patients treated with prolonged methylprednisolone.26 The results of the study were subject to scrutiny due to the small sample size (n = 8) of the control group, signi cant crossover into the methylprednisolone group (all of whom died), and a rel- atively large mortality rate of 60%. Subsequently, in 2006 the ARDS Network addressed the role of corticosteroid administration late in ARDS with the Late Steroid Rescue Study (LaSRS) in which 180 patients were randomized to methylprednisolone administration 7 to 28 days after diag- nosis of ARDS. Administration of methylprednisolone was not linked with signi cant reduction in mortality ( g. 1).27 Furthermore, patients who started steroid treatment after 14 days of diagnosis experienced increased mortality.

Based on the postulate that, compared to other cor- ticosteroids, dexamethasone has an improved potency, lengthened duration of action, and weak mineralocorticoid e ect, Villar et al. performed a prospective trial random- izing ARDS patients to receive either dexamethasone or placebo.28 Compared to patients in the control group, the dexamethasone treatment group showed a reduced time on mechanical ventilation and 60-day mortality; however, drug allocation and data analysis were performed in an unblinded fashion, potentially leading to bias. Furthermore, 250 patients were excluded for already receiving steroids before randomization, indicating that participating phy- sicians already favored the use of corticosteroids, which might have in uenced clinical decisions to modify mechan- ical ventilation duration. In summary, guidelines support- ing routine glucocorticoid administration in ARDS based on rigorously performed randomized controlled trials are currently not supporting their use. However, as discussed later in this review in the section of “Steroids in COVID-19 ARDS”, dexamethasone treatment has been the rst ther- apy to show mortality improvement in mechanically venti- lated COVID-19 patients.29

Conservative Oxygenation

Among the most common therapies implemented in criti- cally ill patients and nearly all ARDS patients is the supple- mental provision of oxygen. Oxygen is frequently delivered generously in order to increase Pao2, and oftentimes patients become hyperoxic while attempting to reverse tissue hypoxia. However, evidence indicates that liberal oxygen use is associated with vasoconstriction, decreased cardiac output, absorption atelectasis, increased proin ammatory responses, and increased mortality.30,31 As such, establish- ing a protocol of oxygen treatment that balances essen- tial delivery to organs while preventing excessive harmful e ects of hyperoxia has been an important subject of recent

investigations ( g. 1). In a single-center randomized trial published in 2016, critically ill intensive care unit patients with a length of stay of 3 days or longer who were assigned to receive conservative oxygen therapy (Pao2 between 70 and 100 mmHg) had lower mortality than those who received more conventional care (Pao up to 150 mmHg).32

Conservative Oxygenation in Acute Respiratory Distress Syndrome (LOCO2) trial, Barrot et al. recruited ARDS patients to conservative (oxygen saturation measured by pulse oximetry [Spo2] between 88 and 92%) or liberal (Spo2 greater than 96%) oxygen treatment arms. The trial was terminated early due to an associated increase in mortality at 28 days and ve episodes of mesenteric ischemia in the conservative oxygen treatment group.33 Worse outcomes in conservative oxygenation may be attributed to the deteri- orated gas exchange in ARDS patients, making them more prone to hypoxemia in the conservative oxygen treatment arm. Going forward, trials will need to carefully assess how to determine target oxygenation levels (e.g., Spo2 and Pao2 targets, measurements from mixed venous blood, di erent targets for di erent organ injuries) to better answer how oxygen concentrations are selected.

Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation is a rescue ther- apy that has been employed in ARDS patients who fail to improve on mechanical ventilation management and as a means to avoid potential injurious aspects of venti- lator-associated lung injury. Advances in extracorporeal membrane oxygenation delivery have been associated with an increase in the number of centers and cases using it, particularly since the 2009 in uenza A virus subtype (H1N1) in uenza pandemic.34 Investigators from the 2009 Conventional Ventilatory Support versus Extracorporeal Membrane Oxygenation for Severe Adult Respiratory Failure (CESAR) trial group sought to answer whether the use of extracorporeal membrane oxygenation during severe ARDS would provide a survival bene t when com- pared to conventional support by mechanical ventilation ( g. 1).35 The results of the trial indicated that there was a survival bene t in favor of patients being randomized to extracorporeal membrane oxygenation treatment, but this di erence was not statistically signi cant. Furthermore, the study was impaired by the use of heterogeneous mechanical ventilation strategies in the control group (including the use of large tidal volumes). Additionally, a large percentage of patients in the extracorporeal membrane oxygenation group who were transferred to extracorporeal membrane oxygenation–capable hospitals never received extracor- poreal membrane oxygenation, allowing for the potential confounding e ects attributed to the fact that extracorpo- real membrane oxygenation–capable hospitals may attain enhanced ARDS survival regardless of whether patients actually received extracorporeal membrane oxygenation.A

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2
A more recent study, the 2020 Liberal Oxygenation versus

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subsequent international multicenter study was conducted to speci cally address weaknesses of previous trials imple- menting extracorporeal membrane oxygenation in early severe ARDS, the 2018 ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial.36 Despite achieving a high quality of control for ventilation strategies in both groups and nearly universal implementation of extracorporeal membrane oxygenation in patients randomized to receive it, the results demonstrated that there was no signi cant di erence in mortality between the extracorporeal mem- brane oxygenation group and the control group. Given the lack of strong evidence supporting the use of extracorpo- real membrane oxygenation as a routine early treatment for ARDS, it is recommended that extracorporeal membrane oxygenation is reserved as rescue therapy in patients who remain hypoxemic despite conventional evidence-based approaches.

Other Investigated Therapeutic Approaches

A large number of pharmacologic approaches have been tested in large, randomized controlled trials in order to improve clinical outcomes in patients with ARDS. These trials have included approaches such as the use of β2-adren- ergics, ketoconazole, lisofylline, vitamin C and D, omega fatty acids, restrictive uid administration, and statins ( g. 1 and table 1).37–49 Although none of these trials have demon- strated a mortality bene t in ARDS patients, it should be highlighted that recent advancements in our understand- ing of ARDS pathophysiology indicate that there are likely important subtypes of injury that predict bene cial response to particular therapies.50 Appropriate identi ca- tion and selection of patients with speci c subphenotypes of ARDS may allow for a targeted approach to e ective treatments and more e cient clinical trials.

aRDs in CoviD-19

ARDS in COVID-19 patients ( g. 2) presents with sev- eral unique characteristics that are not regularly described in non–COVID-19–associated ARDS. Among these char- acteristics is the signi cant development of microvascu- lar thrombosis within the lung vasculature that contributes to ventilation-perfusion mismatch and right ventricular stress.5,51,52 Although the cause for widespread activation of the coagulation cascade is not yet fully understood, dysreg- ulated in ammation and direct injury to endothelial cells by SARS-CoV-2 contribute to the development of micro- thrombotic immunopathology.51–53 Additionally, endothelial cell damage in SARS-CoV-2 infection impairs pulmonary vasoconstriction that normally occurs in response to hypoxia to restrict blood ow to poorly ventilated areas of the lung. Disruption in this physiologic adaptation in COVID-19 patients results in shunting of blood.To this end, treatment for COVID-19–related ARDS has been focused on mitigation of these drivers of disease pathophysiology through the use of antivirals, steroids, anticoagulants, and prone positioning.

Antiviral Therapy

The use of antiviral therapeutics in COVID-19–related ARDS is an approach that has gained tremendous e ort and attention.Their mechanisms of action are directed at speci c viral components that are necessary for SARS- CoV-2 replication and pathogenicity. In this way, antivi- rals are unique in that they target the inciting virus instead of host-related factors, such as tissue in ammation and immune cell functions, to prevent lung injury and subse- quent excessive in ammation. Remdesivir, an inhibitor of viral RNA-dependent RNA polymerase, is perhaps the most noted antiviral currently under investigation.54 In mere months after the emergence of SARS-CoV-2, Beigel et al. published the preliminary results of the Adaptive COVID-19 Treatment Trial (ACTT-1), a large randomized, placebo-controlled trial for the antiviral drug remdesivir.55 The results demonstrate a statistically signi cant reduction in time to recovery in severe COVID-19 patients who received remdesivir.The shortened time to recovery e ect was strongest in the early severe disease group (patients requiring oxygen, but not yet intubated), which likely indi- cates that the timing of administration will be critical for future use. Unfortunately, the trial did not demonstrate e cacy for remdesivir in patients who began treatment after already requiring mechanical ventilation. Indeed, the follow-up time may have been too short to evaluate these patients, and the results for the complete cohort are still pending.

Additional antiviral treatments that have been proposed for the treatment of hospitalized COVID-19 patients include hydroxychloroquine, an antimalarial drug, and lopinavir-ritonavir, a protease inhibitor cocktail used for treating human immunode ciency virus. Indeed, both drugs have demonstratable e cacy in reducing SARS- CoV-2 infection in vitro, but both have failed to translate into therapeutic results in COVID-19 patients.56–58 On June 29, 2020, the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial terminated its lopinavir-ri- tonavir arm due to lack of clinical bene t (http://www. recoverytrial.net/results/lopinavar-results, accessed July 5, 2020). Similarly, on June 20, 2020, the National Institutes of Health PETAL Network halted its trial investigating hydroxychloroquine use (http://www.nih.gov/news- events/news-releases/nih-halts-clinical-trial-hydroxychlo- roquine, accessed July 5, 2020).

Anticoagulation and Thrombolytics

Given that a key pathologic nding in COVID-19 is the prevalence of thrombotic coagulopathy within lung vas- culature, a great deal of attention has been directed at whether anticoagulation or thrombolytic therapy may pro- vide therapeutic e cacy in COVID-19 ARDS. Indeed, a French multicenter prospective study identi ed a statis- tically signi cant increase in thromboses in COVID-19– related ARDS when compared with a historic cohort in

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Fig. 2. Pathophysiology of acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19). Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection is mediated by virus spike binding to angiotensin converting enzyme–2 on type 2 alveolar epithelial cells.78,79 Viral infection prompts cells to react by releasing chemokines and cytokines.80 Infection can also overwhelm epithelial cells and cause them to die via pyroptosis, which results in the release of in ammatory damage and pathogen–associated molecular patterns. Recognition of damage and pathogen–associated molecular patterns and cytokines activates alveolar macrophages and chemokines act to recruit in ammatory immune cells to the lung. Excessive immune cell release of antimicrobial effectors, such as metallomatrix proteases, elastases, and reactive oxygen species, induce collateral tissue injury that results in loss of epithelial and endothelial barrier integrity and in ltration of proteinaceous uid into the alveolar airspace.80 Furthermore, increasing evidence supports the important role of endothelial cells in the initiation of in ammation and the development of extensive pulmonary intravascular coagulopathy that is common in COVID-19 patients.51–53 In severe cases, patients with COVID-19 have developed disseminated intravascular coagulopathy.81 Components of the gure were modi ed from SMART Servier Medical Art Library.

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non–COVID-19 ARDS.59 Although there is currently a lack of evidence from randomized control trials that support the use of intermediate or treatment-level doses of prophy- lactic anticoagulation, some centers have adopted the use of such strategies. In an early Chinese retrospective analysis of severe COVID-19, anticoagulation therapy was associated with reduced 28-day mortality.60 Furthermore, in another retrospective observational study of 2,773 patients hospital- ized for COVID-19 in New York City, patients receiving mechanical ventilation (n = 395) had signi cantly reduced in-hospital mortality when treated with treatment-dose lev- els of anticoagulation (29.1% vs. 62.7%).61 In light of these observations and the current recognition for the pathophysi- ologic role for coagulopathy in SARS-CoV-2 infection, sev- eral clinical trials aimed at ascertaining the role of empiric therapeutic dosing with anticoagulation in COVID-19 ARDS have been initiated.

In addition to anticoagulation, thrombolytic treatment in COVID-19 ARDS patients has been proposed as a salvage therapy. Current evidence for the use of thrombolytic treat- ment in ARDS is limited to a 2001 phase I trial in which 20 patients with severe ARDS were treated with urokinase, which demonstrated improved oxygenation and no risk of bleeding.62 Indeed, some groups have published case series for patients with COVID-19 ARDS who were treated with salvage antithrombolytic agents.63–65 All patients had some level of improvement in oxygenation and/or hemodynam- ics after the administration of tissue plasminogen activator, but in most cases, patients ultimately died. Nonetheless, the scienti c rationale for using brinolytic therapy in COVID-19 ARDS—namely, the consistent ndings of pulmonary microvascular thrombosis—has resulted in the initiation of urgently needed clinical trials studying the role of antithrombotic agents in COVID-19 ARDS.66

Prone Positioning in COVID-19 ARDS

Based on the signi cant prevalence for ventilation-perfu- sion mismatch as a result of microvascular thromboses in COVID-19 patients, prone positioning in mechanically ventilated patients is recommended in order to improve lung recruitability and oxygenation.67–70 In a detailed char- acterization of mechanically ventilated COVID-19 patients in two hospitals in Boston, Massachusetts, patients who underwent prone positioning had increased median Pao2/ Fio2 ratios from 150 to 232, an improvement that persisted 72h later when Pao2/Fio2 ratios of 233 were measured while patients were supine.71 Although there are cur- rently not enough data to conclude that prone positioning improves long-term outcomes and mortality in mechani- cally ventilated patients, the National Institutes of Health COVID-19 treatment guidelines currently suggest its use.72

Steroids in COVID-19 ARDS

Recent data from the United Kingdom Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial

investigating the use of dexamethasone in hospitalized COVID-19 patients have demonstrated that dexamethasone is the rst drug to improve mortality.29 Mechanically venti- lated patients who were randomized to receive 6mg once per day for 10 days were found to have a reduction of mor- tality by one third when compared to patients who under- went usual care. Interestingly, this mortality bene t was not observed in patients who did not require respiratory support. In response to these ndings, current COVID-19 treatment guidelines from the National Institutes of Health recommend its use in patients who are mechanically ventilated or require oxygen supplementation.72 Moreover, similar to ARDS and PETAL Network studies, the RECOVERY trial provides an example of the power of organized multicenter investi- gations for new treatment approaches in critically ill patients, especially those with ARDS. Moving forward, data from the dexamethasone arm are likely to reinvigorate studies for its use in non–COVID-19 ARDS patients that may support the open-label dexamethasone studies previously mentioned.28

Conclusions

The past 25 yr of large, randomized clinical trial e orts have contributed a tremendous amount of insight that has advanced the clinical practice of lung-protective mechani- cal ventilation. Indeed, implementation of clinically proven management interventions, such as the use of low tidal vol- umes and prone positioning, has dramatically improved the outcomes for ARDS. However, mortality remains high, and there is a lack of targeted treatment options. Nonetheless, emerging basic science research has resulted in novel ther- apeutic targets, such as hypoxia, adenosine, and microRNA signaling, that might pave the way for new pharmacologic ARDS treatments. Advancements in our appreciation for pathologic and clinical subtypes of ARDS will likely also play a critical role in designing clinical trials to identify e – cacy for treatments in speci c cohorts of ARDS patients.50 Furthermore, the recent COVID-19 pandemic has stimu- lated the rapid initiation of clinical trials aimed at target- ing ARDS. At the time of this writing, there are over 100 registered controlled trials for COVID-19 ARDS listed on ClinicalTrials.gov. Potential interventions that demon- strate clinical e cacy in COVID-19 ARDS could also pro- vide usefulness in treating ARDS patients independent of SARS-CoV-2 infection. It is important to note, however, that insights gained from proven therapies for COVID-19 ARDS could translate to non–COVID-19 ARDS subtypes that share pathophysiologic components with COVID-19 cases. For example, the e cacy reported with dexametha- sone could indicate speci c use for patients with viral-as- sociated ARDS who are characterized by immune pro les similar to what is seen in COVID-19 and not for patients with other etiologic types of ARDS. Additional clinical studies will be required to carefully address such hypothe- ses. Last, to establish e cacy for novel ARDS interventions, collaborative e orts, such as the multicenter trials ongoing

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in the PETAL Network, will continue to be vital for the successful improvement of ARDS outcomes. In addition to these large-scale studies, a network of smaller clinical trials investigating the e cacy of novel treatment concepts73,74 may be required to identify new approaches for ARDS therapy. Channeling enthusiasm for new trials targeting COVID-19 ARDS may provide a catalyst and framework for these important collaborations going forward.

Research Support

Supported by grant No.T32GM120011 from the National Institutes of Health (Bethesda, Maryland; to Mr. Berg); unrestricted grant from the American Thoracic Society (New York, New York); grant No. 19CDA34660279, an American Heart Association (Dallas, Texas) Career Development Award; grant No. CA-622265, an American Lung Association (Chicago, Illinois) Catalyst Award; grant No. 1UL1TR003167–01, a Center for Clinical and Translational Sciences, McGovern Medical School (Houston,Texas) Pilot Award; a Parker B. Francis Fellowship (Kansas City, Missouri; to Dr.Yuan); and National Institutes of Health (Bethesda, Maryland) grant Nos. R01-DK097075, R01-HL098294, POI-HL114457, R01-DK082509, R01-HL109233, R01-DK109574, R01-HL119837, and R01-HL133900 (to Dr. Eltzshig).

Competing Interests

Dr.Williams is a scienti c speaker about sugammadex for Merck Pharmaceuticals (Kenilworth, New Jersey). The other authors declare no competing interests.

Correspondence

Address correspondence to Dr. Yuan: Department of Anesthesiology, University of Texas Health Science Center at Houston, McGovern Medical School, 6431 Fannin Street, Houston, Texas 77030. Xiaoyi.Yuan@uth.tmc.edu. Anesthesiology’s articles are made freely accessible to all readers on http://www.anesthesiology.org, for personal use only, 6 months from the cover date of the issue.

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